This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population. Thus far, 749 subjects have been enrolled, including 478 recombinant immunoblot assay (RIBA) positives, 54 RIBA indeterminates, and 217 RIBA-negative controls. The early data have been published (New England Journal of Medicine 334:1691,1996) and the trends have remained the same over time. Unexpected findings were the high proportion (41 percent) of RIBA+ donors who admitted to prior (remote) intravenous drug use and the strong independent association between cocaine snorting and HCV positivity. Shared paraphernalia for snorting accompanied by epistaxis, may serve as a covert vehicle for parenteral viral transmission. Among anti-HCV+/RIBA-positive donors, 82 percent were persistently viremic, but 18 percent appeared to have recovered from prior HCV infection. A liver biopsy has been obtained from 186 (47%)patients who were chronically infected; 51% had mild chronic hepatitis and 44% had moderate chronic hepatitis; despite a mean duration of infection of 20 years,only 5% had severe inflammation. No fibrosis was observed in 33% of biopsied patients and 52% had only mild fibrosis; 15 had more severe fibrosis including 13% with bridging fibrosis and 2% with cirrhosis. Overall, HCV infection in this cohort was generally asymptomatic and clinically benign. Despite an association of HCV with sexually promiscuous practices, we found no evidence for sexual transmission to the specific partners of 165 HCV-infected individuals. The study continues to follow the natural history HCV infection and is now focusing on histologic progression as assessed in liver biopsies obtained at 5-year intervals. New emphasis is being placed on studies of cell-mediated immune responses to HCV and of treatment responses. The 15-year experience with this cohort is being analyzed for publication.